Understanding mechanisms by which synapses are modified for long-term memory storage is crucial for explaining normal brain function as well as diseases and disorders of the brain. Many studies have established that new gene expression and new protein synthesis are critical for synaptic changes that underlie long-term memory. Recent studies indicate that proteolysis by the ubiquitin-proteasome pathway plays a critical role in long-term synaptic plasticity. The goal of this proposal is to elucidate the spatial and temporal roles of the proteasome and the interplay between protein synthesis and degradation in long-term synaptic plasticity We will use a highly suitable model system of mammalian long-term synaptic plasticity, late phase long-term potentiation (L-LTP) in the hippocampus. Our results show that inhibition of the proteasome enhances the early, translation-dependent induction part of L-LTP but inhibits the transcription-dependent maintenance phase of L-LTP. Proteasome-mediated enhancement of early part of L-LTP depends on NMDA receptor and cAMP-dependent protein kinase. Our data indicate that proteasome inhibition increases induction of L-LTP by stabilizing the locally synthesized proteins in the dendrites but interferes with local translation at later stages. Our results also show that inhibition of proteasome blocks transcription of brain-derived neurotrophic factor (BDNF), which is a cAMP-responsive element binding protein (CREB)-inducible gene. Furthermore, our results show that proteasome inhibitors block degradation of ATF4, a CREB repressor that is known to suppress L-LTP and memory. Thus, proteasome inhibition appears to block maintenance of L-LTP by hindering CREB-mediated transcription. Our first aim is to investigate the mechanism by which L-LTP induction is enhanced by proteasome inhibition and to identify the newly synthesized proteins stabilized by the proteasome. Under our second aim, we will test the idea that blockade of the proteasome impairs the maintenance of L-LTP by causing a buildup of negative regulators of plasticity such as translation repressors and by hindering transcription in the nucleus. Using a powerful combination of proteomic, molecular biological and electrophysiological studies the proposed experiments will address important, unanswered questions pertaining to the relationship between proteolysis and protein synthesis in long-term synaptic plasticity. PUBLIC HEALTH RELEVANCE: Memories form when connections between nerve cells called synapses change. Recent discoveries show that regulation of proteins in the nerve cells by degradation plays a role in memory. Proteins are degraded by a part of the cell named proteasome when they are tagged by a little molecule called ubiquitin. Protein degradation is abnormal in many diseases and disorders of the brain. This research could help explain the memory loss that occurs in brain diseases and memory loss that happens in old age.